A family of double-homeodomain transcription factors promotes zygotic genome activation in placental mammals [ChIP-seq_d1]. Homo sapiens

In metazoans, the fertilized embryo is transcriptionally mostly silent for a few cell divisions, until release of a first major wave of embryonic transcripts by so-called zygotic genome activation (ZGA). Maternally provided ZGA-triggering factors have been identified in Drosophila melanogaster and Danio rerio but their mammalian homologues are still undefined. Here, we reveal that DUX family transcription factors are key to this process in human and mouse. First, human Dux4 and murine Dux are expressed prior to ZGA in both species. Second, both orthologues bind to and activate the promoters of ZGA genes. Third, Dux knockdown hinders the progression of mouse embryos beyond the 2-cell stage. Fourth, it prevents the cycling of mouse embryonic stem (ES) cells through a 2-cell-like state whereas, conversely, Dux overexpression induces the accumulation of these ZGA genes-expressing ES cells. We conclude that DUX proteins are master regulators of mammalian ZGA. Overall design: ChIP-sequencing analysis of DUX4 ectopically expressed in human embryonic stem cells

在多细胞动物（metazoans）中，受精卵在最初的数次细胞分裂过程中基本处于转录沉默状态，直至所谓的合子基因组激活（zygotic genome activation, ZGA）释放首批主要的胚胎转录本。在黑腹果蝇（Drosophila melanogaster）和斑马鱼（Danio rerio）中，母体提供的合子基因组激活触发因子已被鉴定，但它们在哺乳动物中的同源因子仍未明确。本研究揭示，DUX家族转录因子是人类与小鼠中该过程的关键调控因子。其一，人类DUX4与小鼠Dux在两个物种的合子基因组激活前均有表达；其二，二者的直系同源蛋白均可结合并激活合子基因组激活相关基因的启动子；其三，敲低Dux会阻碍小鼠胚胎突破2细胞期进程；其四，该操作会阻止小鼠胚胎干细胞（embryonic stem cells, ES cells）进入2细胞样状态循环；反之，过表达Dux则会诱导表达这些合子基因组激活基因的胚胎干细胞富集。综上，我们认为DUX蛋白是哺乳动物合子基因组激活的核心调控因子。整体实验设计：对异位表达DUX4的人类胚胎干细胞进行染色质免疫共沉淀测序（ChIP-sequencing）分析。